Age-related human diseases including cancer, Alzheimer's and Parkinson's disease show a clear correlation with mitochondrial dysfunction and reactive oxygen species (ROS). We propose to undertake a combined genetic, biochemical and bioenergetics approach to test the hypothesis that mitochondrial dysfunction and particularly mitochondrial reactive oxygen species (ROS) generation are causatively involved in age related disease. We propose to use three main manipulations of mitochondrial features-electron transport chain complexes, the glutathione pool and superoxide levels-and to measure outcomes models of these three age-related conditions. We believe that the proposed Program Project will make a significant contribution to our understanding of how mitochondrial function contributes to age-related disease with a view towards designing successful interventions.